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Prenatal LPS exposure alters the dev...

Monahan, Angela Jean.

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Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors./
Author:	Monahan, Angela Jean.
Description:	175 p.
Notes:	Source: Dissertation Abstracts International, Volume: 71-04, Section: B, page: 2201.
Contained By:	Dissertation Abstracts International71-04B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3401879
ISBN:	9781109695120

Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors.
Monahan, Angela Jean.

Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors. - 175 p.

Source: Dissertation Abstracts International, Volume: 71-04, Section: B, page: 2201.

Thesis (Ph.D.)--Rush University, 2010.

Parkinson's disease is a movement disorder in which there are approximately 50,000 newly diagnosed cases each year. The cause of non-familial Parkinson's disease, however, is unknown although several studies implicate environmental neurotoxins as a causative agent. The majority of these studies, however, focus on adult exposures. Data from our laboratory as well as others suggests a role for prenatal exposures in the etiology of Parkinson's disease. In our laboratory, gravid female rats which were treated with the Escherichia coli lipopolysaccharide (LPS) bacteriotoxin produced offspring born with fewer DA neurons (Ling, Z, 2002). These offspring have less striatal DA, an increase in DA activity ([HVA]/[DA]), and neuroinflammatory changes that persisted up to 16 months at which time there was presence of Lewy-like bodies in brain (Ling et al., 2002c; Carvey et al., 2003; Ling et al., 2004). To date, our data has demonstrated that these changes are already present by E18, suggesting that the mechanism(s) responsible for these changes occur(s) earlier in development. We proposed in this thesis to test the hypothesis that prenatal LPS exposure leads to elevated levels of pro-inflammatory cytokines within the developing nigro-striatal pathway which, in turn, reduces levels of neurotrophic factors (NTF(s)) essential for the development of the pathway. From the studies designed to address this hypothesis, it was revealed that prenatal LPS exposure at E10.5 reduced DA cell survival and process length of cells harvested at E14.5 and grown in vitro for seven days. Conditioned media studies further suggested that there was an alteration within the neurotrophic environment of the developing nigrostriatal pathway that may have been responsible for the results observed in vitro. Additional studies indicated that prenatal LPS exposure produced an increase in IL-6, IL-1beta and TNF-alpha in maternal serum and amniotic fluid by 2 hours post exposure and elevations in IL-1beta in embryo brain by 6 hours post exposure. By E14.5, it was shown that prenatal LPS exposure produced a reduction in mRNA in glial derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) accompanied by a reduction in GDNF protein but an elevation in BDNF protein. To better understand the relationship between proinflammatory cytokines and NTFs, VM-ST co-cultures were treated with IL-6, IL-1beta and TNF-alpha and after 24 hours cultures were assessed for changes in GDNF and BDNF secreted protein. The data showed that at the highest doses of IL-1beta treatment, GDNF was significantly increased in the media. Taken together these data support the association between elevations in proinflammatory cytokines which are known to occur in Parkinson's disease and alterations in NTFs which are known to be reduced in Parkinson's disease. Given that NTFs such as GDNF are currently being studied as a treatment option for Parkinson's disease patients, further study into the role proinflammatory cytokines play in regulating expression of GDNF is warranted.

ISBN: 9781109695120Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors.
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245 1 0 $a Prenatal LPS exposure alters the development of the nigrostriatal pathway by disrupting neurotrophic factors.
300 $a 175 p.
500 $a Source: Dissertation Abstracts International, Volume: 71-04, Section: B, page: 2201.
500 $a Adviser: Paul M. Carvey.
502 $a Thesis (Ph.D.)--Rush University, 2010.
520 $a Parkinson's disease is a movement disorder in which there are approximately 50,000 newly diagnosed cases each year. The cause of non-familial Parkinson's disease, however, is unknown although several studies implicate environmental neurotoxins as a causative agent. The majority of these studies, however, focus on adult exposures. Data from our laboratory as well as others suggests a role for prenatal exposures in the etiology of Parkinson's disease. In our laboratory, gravid female rats which were treated with the Escherichia coli lipopolysaccharide (LPS) bacteriotoxin produced offspring born with fewer DA neurons (Ling, Z, 2002). These offspring have less striatal DA, an increase in DA activity ([HVA]/[DA]), and neuroinflammatory changes that persisted up to 16 months at which time there was presence of Lewy-like bodies in brain (Ling et al., 2002c; Carvey et al., 2003; Ling et al., 2004). To date, our data has demonstrated that these changes are already present by E18, suggesting that the mechanism(s) responsible for these changes occur(s) earlier in development. We proposed in this thesis to test the hypothesis that prenatal LPS exposure leads to elevated levels of pro-inflammatory cytokines within the developing nigro-striatal pathway which, in turn, reduces levels of neurotrophic factors (NTF(s)) essential for the development of the pathway. From the studies designed to address this hypothesis, it was revealed that prenatal LPS exposure at E10.5 reduced DA cell survival and process length of cells harvested at E14.5 and grown in vitro for seven days. Conditioned media studies further suggested that there was an alteration within the neurotrophic environment of the developing nigrostriatal pathway that may have been responsible for the results observed in vitro. Additional studies indicated that prenatal LPS exposure produced an increase in IL-6, IL-1beta and TNF-alpha in maternal serum and amniotic fluid by 2 hours post exposure and elevations in IL-1beta in embryo brain by 6 hours post exposure. By E14.5, it was shown that prenatal LPS exposure produced a reduction in mRNA in glial derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) accompanied by a reduction in GDNF protein but an elevation in BDNF protein. To better understand the relationship between proinflammatory cytokines and NTFs, VM-ST co-cultures were treated with IL-6, IL-1beta and TNF-alpha and after 24 hours cultures were assessed for changes in GDNF and BDNF secreted protein. The data showed that at the highest doses of IL-1beta treatment, GDNF was significantly increased in the media. Taken together these data support the association between elevations in proinflammatory cytokines which are known to occur in Parkinson's disease and alterations in NTFs which are known to be reduced in Parkinson's disease. Given that NTFs such as GDNF are currently being studied as a treatment option for Parkinson's disease patients, further study into the role proinflammatory cytokines play in regulating expression of GDNF is warranted.
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